atualização Glucocorticoid-Remediable Aldosteronism

Graham T. McMahon ABSTRACT Robert G. Dluhy Glucocorticoid-remediable aldosteronism (GRA) is a monogenic form of human that predisposes to cerebral hemorrhage. As a result of a chimeric gene duplication, is ectopically synthesized in the -secreting zona fasciculata of the under the control of adrenocorticotropin (ACTH). Hypertension frequently has its onset during childhood and is usually refractory to standard anti-hypertensives such as ACE inhibitors and - b l o c k e r s . can develop in those treated with a -wasting diuretic, but random potassium levels are usually normal. Diagnosis has been facilitated by the availability of a genetic test. Suppression of ACTH release with exogenous is a useful diagnos- tic and therapeutic strategy. Treatment with the receptor antagonists and epleronone is also effica- cious. The diagnosis of GRA facilitates directed therapies and screen- ing of at-risk individuals and kindreds. (Arq Bras Endocrinol Metab 2 0 0 4 ; 4 8 / 5 : 6 8 2 - 6 8 6 )

Keywords: Glucocorticoid-remediable aldosteronism; Dexamethasone- suppressible ; Monogeneic hypertension; Hyperal- dosteronism

RESUMO Division of , Diabetes & Hypertension, Brigham Aldosteronismo Remediável por Glicocorticóide. & Women’s Hospital & Harvard Aldosteronismo remediável por glicocorticóides (GRA) é uma forma Medical School, Boston, Massachu - monogênica de hipertensão humana com predisposição para a hemorragia cerebral. Como resultado da duplicação de um gene setts, USA. quimérico, aldosterona passa a ser sintetizada ectopicamente na zona fasciculada do córtex adrenal, secretora de cortisol, sob o controle da adrenocorticotrofina (ACTH). O início da hipertensão ocorre freqüente- mente durante a infância e é usualmente refratária aos anti-hiperten- sivos habituais, como os inibidores da ECA e - b l o q u e a d o r e s . Hipocalemia pode se manifestar naqueles tratados com diuréticos espoliadores de potássio, mas os níveis basais de potássio são usual- mente normais. O diagnóstico tem sido facilitado pela disponibilidade de um teste genético. A supressão da liberação de ACTH com dexam- etasona exógena é uma estratégia útil para o diagnóstico e a ter- apêutica. Tratamento com antagonistas do receptor mineralocor- ticóide, espironolactona e epleronona, também é eficaz. O diagnósti- co de GRA facilita a terapia direcionada e o rastreamento de indivídu- os e familiares de risco para a doença. (Arq Bras Endocrinol Metab 2004;48/5:682-686)

Descritores: Aldosteronismo remediável por glicocorticóide; Hiperal- dosteronismo supressível por dexametasona; Hipertensão monogêni- ca; Hiperaldosteronismo Recebido em 02/07/04 Aceito em 12/07/04

682 Arq Bras Endocrinol Metab vol 48 nº 5 Outubro 2004 Glucocorticoid-Remediable Aldosteronism McMahon & Dluhy

OLLOWING SUTHERLAND’S initial description of a ylates corticosterone in the zona glomerulosa (figure 1). In con- Ffather and son with an autosomal dominant trast, the synthesis of cortisol requires hydroxylation of preg- hypokalemic hypertensive syndrome in 1966 (1), clin- nenolone by 17-hydroxylase, which is expressed only in the icians began to report other kindreds with biochemical zona fasciculata and is regulated by adrenocorticotropin features of primary hyperaldosteronism (2). Though ( A C T H ) . these individuals had hypertension, suppressed plasma activity, and hypokalemia, they differed from Aldosterone increases resorption and others with hyperaldosteronism since their hyperten- potassium excretion in the distal tubules and cortical col- sion and hyperaldosteronism were reversed by the lecting ducts of the , thereby regulating circulating administration of glucocorticoids. The disorder potassium concentrations as well as intravascular volume became known as glucocorticoid-remediable aldos- (3). Hyperaldosteronism therefore results in volume teronism (GRA). GRA has now been identified across expansion, hypertension and usually hypokalemia. Such the world, and its molecular etiology is fully character- volume expansion acts to suppress the renin- ized. GRA appears to be the commonest monogenic form of human hypertension. system resulting in the characteristic increase in the plasma aldosterone (PA) to plasma renin activity (PRA) ratio. The majority of patients with primary hyperaldosteronism are PATHOPHYSIOLOGY found to have either a unilateral aldosterone-producing adrenal or bilateral idiopathic . In The is composed of three distinct zones respon- contrast, patients with GRA have hyperaldosteronism as a sible for producing different steroid . Aldosterone is result of abnormal regulation of secretion by physiologic secreted by the zona glomerulosa, cortisol from the zona fasci - levels of ACTH. c u l a t a, and androgens/estrogens from the zona reticularis. The first steps of aldosterone biosynthesis from cholesterol to GENETICS progesterone are identical to those required for the biosynthe- sis of cortisol. Thereafter, the metabolic pathways diverge: The genes for and 11 -hydroxy- aldosterone synthase, regulated by angiotensin II, 18-hydrox-  lase are located in close proximity on the long arm of

Table 1. Algorithm for GRA diagnosis and treatment. Screening Recommended for hypertensive individuals who: - are diagnosed with primary hyperaldosteronism without demonstrable tumor - are young (especially children) and have suppressed plasma renin activity - have a family history of cerebral hemorrhage or hypertension before age 30 years - have refractory hypertension (hypertensive on 3 classes of agents including a diuretic) - are members of known GRA kindreds

Diagnosis Dexamethasone suppression test Easily performed. Dexamethasone 0.5mg every 6hrs x 2 days, normally aldosterone

< 4ng/dl on day 3 at 8am Genetic Test Can be arranged through the international GRA registry (http://www.brighamandwomens.org/gra) 24 hour urinary 18-hydroxycortisol & Impractical since assays only available in specialized centers. Elevated > 2x upper limit 18-oxocortisol levels of normal; a urinary level of 18-hydroxycortisol > 10nmol/l is diagnostic (5)

Treatment Glucocorticoids Dexamethasone 0.125-0.25mg, or prednisolone 2.5-5mg daily, titrated to normotension. Mineralocorticoid receptor antagonists and spironolactone are effective treatment choices. Sodium epithelial channel antagonists Amiloride and triamterene have also been used successfully. Non-directed anti-hypertensives -blockers and ACE-inhibitors are less likely to be efficacious in the setting of a sup- pressed renin-angiotensin system (9). Dihydropyridine calcium channel blockers can be useful adjunctive treatments to the above diuretic agents. Arq Bras Endocrinol Metab vol 48 nº 5 Outubro 2004 683 Glucocorticoid-Remediable Aldosteronism McMahon & Dluhy

chromosome 8 and have identical intron-exon struc- reported pedigrees, and no cases have been reported tures. The two genes share 95% sequence homology among blacks (7). but are usually only expressed in their respective adrenal zones under separate regulation by angiotensin CLINICAL FEATURES II and ACTH, respectively. Subjects with GRA have two normal copies of GRA is an autosomal-dominant disorder and is the most genes encoding aldosterone synthase and 11- common monogenic cause of human hypertension. GRA hydroxylase, but they also have an abnormal gene is usually characterized by severe hypertension, s o d i u m duplication. This hybrid, or chimeric, gene combines retention and suppressed plasma renin activity (8). Unlike the ACTH-responsive promoter sequence of the 11- other mineralocorticoid-excess states, hypokalemia in hydroxylase gene fused to the more distal aldos- the absence of diuretic treatment is uncommon. terone-synthase coding sequence (figure 2). This chimeric gene results from variable, and unequal, Hypokalemia crossing-over between the two genes (4). The vari- Most patients with GRA have normal potassium levels ability of the crossover site suggests that these muta- (8) despite biochemical evidence for primary hyperal- tions arose independently in each pedigree, and did dosteronism. One prospective study in a large pedigree not originate from a single ancestral mutation. As a with GRA (8) revealed that normokalemia was the rule result, aldosterone synthase is ectopically expressed in unless patients had been treated with potassium-wasting the cortisol-producing zone of the adrenal cortex diuretics. Thus, hypokalemia lacks sensitivity as a screen- under the regulation of ACTH. The chimerism also ing test for GRA. The reason why GRA subjects have results in the production of the hybrid steroids 18- normal potassium levels is not understood, but there is oxocortisol and 18-hydroxycortisol that can be used as not renal impairment of the actions of aldosterone. diagnostic aides (5). Genetic analysis of GRA kindreds has revealed Hypertension that the disorder is inherited as an autosomal domi- GRA is usually characterized by severe hypertension nant trait (6). Celtic ancestry is frequent among the with onset early in life (9). In a retrospective report, eighty percent of 20 children under the age of 18 who carried the genetic mutation had hypertension by the age of 13 years; pressures also correlated within sibling pairs. However, only half of the affected chil- dren had severe hypertension ( > 99th centile for age), and 4 of 20 were normotensive (9). A

Figure 1. Normal biosynthetic pathways for cortisol and aldosterone. 11H1 and aldosterone synthase are present only in the zona glomerulosa, and are regulated by angiotensin II. 11H2 is present solely in the zona fascicula - ta and is regulated by ACTH. 21H= 21-hydroxylase. 11H1&2= Figure 2. Chimeric gene duplication in glucocorticoid- 11-hydroxylase isoenzymes 1 & 2; 18 = 18-hydroxylase/ remediable aldosteronism. P= promoter sequence. C= aldosterone synthase. 17H= 17-hydroxylase. coding sequence.

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kindred has been described where only 8 of 21 affect- individuals in one year (16). Genetic screening of ed subjects had systolic blood pressures of greater than random hypertensive individuals by contrast is not 140 and/or diastolic blood pressures of greater than efficacious (16). 90mmHg (10). In other reports (11), all affected The PA/PRA ratio in GRA patients is greater members have been hypertensive. than 30, but this is like other etiologies of primary Possible explanations for this incomplete pene- aldosteronism. Since hypokalemia lacks sensitivity as a trance of hypertension include self-selected dietary salt screening test (8,17), the above historical clues are the restriction, concomitant inheritance of blood pressure- most useful in pointing to a possible diagnosis of GRA. lowering genes, or decreased penetrance of the A number of different strategies can be used to chimeric gene. Data from several GRA kindreds sug- diagnose GRA including the dexamethasone suppres- gest that elevated urinary levels of the vasodilator sion test, measurement of urinary 18-hydroxy/oxo- kallikrein may serve to protect against hypertension steroids (5), or direct genetic analysis (figure 1). (12). Another potential source of phenotypic variation In this disorder the cortisol-producing zona fasci - is linkage disequilibrium with the ‘a’ allele of the c u l a t a ectopically produces aldosterone under the regu- aldosterone synthase gene (13). Individuals inheriting lation of ACTH. As a result, when 0.5mg of the potent the mutation from their mothers were found to have glucocorticoid dexamethasone is given every 6 hours for significantly higher mean arterial pressures without two days, suppression of aldosterone to undetectable higher aldosterone levels. The authors speculated that levels (< 4ng/dl) is seen in GRA subjects (18). On the in-utero exposure to abnormal maternal mineralocor- other hand, in one study, ten percent of sixty patients with ticoid concentrations (14) may up-regulate processes elevated aldosterone levels and a positive dexamethasone responsible for aldosterone responsiveness (13). suppression study had negative genetic testing (19). GRA patients excrete large amounts of urinary Hemorrhagic 18-hydroxycortisol and 18-oxocortisol (5) (so-called In a retrospective study of 27 GRA pedigrees, early ‘hybrid’ steroids) reflecting the action of aldosterone hemorrhagic stroke was a characteristic feature, occur- synthase on cortisol in the zona fasciculata. Very low ring at a mean age of 32 years and associated with high levels are produced in normal subjects, but mild eleva- mortality (61%) (15). In this report, nearly half of all tions occur with aldosterone-producing (7). GRA pedigrees and 18% of all GRA patients demon- Direct screening for the chimeric gene duplica- strated early hemorrhagic as a result of ruptured tion by southern blotting is preferred and is 100% sen- intra-cranial aneurysms. By contrast, there were no sitive and specific for diagnosing GRA and is available strokes in GRA-negative family members. Based on this through the International Registry for Glucocorticoid report, screening with magnetic resonance imaging Remediable Aldosteronism at angiography, beginning at puberty and then every five http://www.brighamandwomens.org/gra. years, has been recommended to detect asymptomatic intra-cranial aneurysms (15). A reduction in event rates as a result of such screening has not been documented. TREATMENT

Non-directed anti-hypertensive therapies are often ineffective DIAGNOSIS in GRA patients (9). Treatment with low dose glucocorticoids is effective (18) by providing feedback suppression of pituitary GRA patients can have mild hypertension and are ACTH release, which suppresses the abnormal regulation of typically normokalemic (8); such patients are often aldosterone secretion. Typical dosing in adults is 0.125- misdiagnosed as having ‘essential’ hypertension. 0.25mg of dexamethasone, or 2.5-5mg of prednisolone daily, Clues pointing to a possible diagnosis of GRA usually administered at bedtime. However, iatrogenic Cush- include early onset of hypertension in youth, a fami- ing’s syndrome and impaired linear growth in children have ly history of early onset hypertension or early cerebral resulted from glucocorticoid overdosing (9). The therapeutic hemorrhage, precipitation of hypokalemia when goal should be normotension, and not normalization of bio- treated with potassium-wasting diuretics, and refrac- chemical markers, such as urinary 18-oxosteroid or serum tory hypertension to standard treatments (figure 2). aldosterone levels, since these remain elevated in the majority Screening targeted at these features performed at one of patients who normalize blood pressure (20). In fact, thera- hypertension clinic discovered two index families and py to normalize laboratory values may unnecessarily increase four further families containing 40 mutation-positive the risk of cushingoid side effects (20).

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The type I mineralocorticoid receptor antago- 9. Dluhy RG, Anderson B, Harlin B, Ingelfinger J, Lifton R. Glucocorticoid-remediable aldosteronism is associated nists, eplerenone and spironolactone, are effective treat- with severe hypertension in early childhood. J Pediatr ment alternatives. Amiloride and triamterene, sodium- 2001;138:715-20. epithelial channel antagonists, have also been used suc- 10. Mulatero P, di Cella SM, Williams TA, et al. Glucocorti- cessfully. Both groups of agents block aldosterone action coid remediable aldosteronism: low morbidity and rather than reducing the production of this mineralocor- mortality in a four-generation Italian pedigree. J Clin Endocrinol Metab 2002;87:3187-91. ticoid. Anti-hypertensives agents, such as -blockers and ACE-inhibitors, are unlikely to be efficacious in the set- 11. O’Mahony S, Burns A, Murnaghan DJ. Dexamethasone- suppressible hyperaldosteronism: a large new kindred. ting of a suppressed renin-angiotensin system (9). How- J Hum Hypertens 1989;3:255-8. ever, dihydropyridine calcium channel blockers can be 12. Dluhy RG, Lifton RP. Glucocorticoid-remediable aldos- useful adjunctive treatments to the above diuretic agents. teronism (GRA): diagnosis, variability of phenotype and regulation of potassium homeostasis. Steroids 1995;60: 48-51. CONCLUSION 13. Jamieson A, Slutsker L, Inglis GC, Fraser R, White PC, Connell JM. Glucocorticoid-suppressible hyperaldos- teronism: effects of crossover site and parental origin of GRA is the commonest monogeneic form of human chimaeric gene on phenotypic expression. Clin Sci hypertension and often masquerades as essential hyper- (Lond) 1995;88:563-70. tension. Clinicians should consider the diagnosis, par- 14 Wyckoff JA, Seely EW, Hurwitz S, Anderson BF, Lifton RP, ticularly in hypertensive children, and those with a fam- Dluhy RG. Glucocorticoid-remediable aldosteronism ily history of either early-onset hypertension or early and pregnancy. Hypertension 2000;35:668-72. cerebral hemorrhage. A dexamethasone suppression test 15. Litchfield WR, Anderson BF, Weiss RJ, Lifton RP, Dluhy RG. can be a useful screening maneuver; genetic screening and Intracranial aneurysm and hemorrhagic stroke in glu- cocorticoid-remediable aldosteronism. H y p e r t e n s i o n the measurement of urinary 18-oxosteroids are diagnos- 1998;31:445-50. t i c . Treatment options include glucocorticoids to sup- 16. Gates LJ, Benjamin N, Haites NE, MacConnachie AA, press ACTH and aldosterone levels, and mineralocorti- McLay JS. Is random screening of value in detecting coid receptor antagonists. Hypertension in GRA subjects glucocorticoid-remediable aldosteronism within a can often be controlled with directed monotherapy. hypertensive population? J Hum Hypertens 2001;15:173-6. 17. Litchfield WR, Coolidge C, Silva P, et al. Impaired potassi- u m-stimulated aldosterone production: a possible REFERENCES explanation for normokalemic glucocorticoid-remedi- able aldosteronism. J Clin Endocrinol Metab 1. Sutherland DJ, Ruse JL, Laidlaw JC. Hypertension, 1997;82:1507-10. increased aldosterone secretion and low plasma renin activity relieved by dexamethasone. Can Med Assoc J 18. Litchfield WR, New MI, Coolidge C, Lifton RP, Dluhy RG. 1966;95:1109-19. Evaluation of the dexamethasone suppression test for the diagnosis of glucocorticoid-remediable aldostero- 2. New MI, Peterson RE. A new form of congenital adrenal nism. J Clin Endocrinol Metab 1997;82:3570-3. hyperplasia. J Clin Endocrinol Metab 1967;27:300-5. 3. White PC. Disorders of aldosterone biosynthesis and 19. Mulatero P, Veglio F, Pilon C, et al. Diagnosis of gluco- action. N Engl J Med 1994;331:250-8. corticoid-remediable aldosteronism in primary aldos- teronism: aldosterone response to dexamethasone and 4. Lifton RP, Dluhy RG, Powers M, et al. A chimaeric 11 long polymerase chain reaction for chimeric gene. J beta-hydroxylase/aldosterone synthase gene causes Clin Endocrinol Metab 1998;83:2573-5. glucocorticoid-remediable aldosteronism and human hypertension. Nature 1992;355:262-5. 20. Stowasser M, Bachmann AW, Huggard PR, Rossetti TR, Gordon RD. Treatment of familial hyperaldosteronism 5. Mosso L, Gomez-Sanchez CE, Foecking MF, Fardella C. type I: only partial suppression of adrenocorticotropin Serum 18-hydroxycortisol in , hyper- required to correct hypertension. J Clin Endocrinol tension, and normotensives. Hypertension 2001;38: 688-91. Metab 2000;85:3313-8. 6. Lifton RP, Dluhy RG, Powers M, et al. Hereditary hyper- tension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase. Nat Genet Endereço para correspondência: 1992;2:66-74. 7. Dluhy RG, Lifton RP. Glucocorticoid-remediable aldos- Graham T. McMahon teronism. J Clin Endocrinol Metab 1999;84:4341-4. Division of Endocrinology Diabetes & Hypertension 8. Rich GM, Ulick S, Cook S, Wang JZ, Lifton RP, Dluhy RG. Brigham & Women’s Hospital Glucocorticoid-remediable aldosteronism in a large 221 Longwood Ave. kindred: clinical spectrum and diagnosis using a char- RFB 2, Boston, MA 02115, USA. acteristic biochemical phenotype. Ann Intern Med Fax: 432-204 0362 1992;116:813-20. e-mail: [email protected]

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